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Vol. 57, Issue 4, 667-678, April 2000
B
Departments of Pediatrics and Pharmacology (O.Z., B.D.S., G.E.G.,
M.B.R), Department of Neurology (J.B.G., J.S.B.), Department of
Neuroscience (W.S.), Children's Hospital of Philadelphia, University
of Pennsylvania, Philadelphia, Pennsylvania; and Department of
Neurology, The Johns Hopkins University, Baltimore Maryland (R.G.,
J.D.R)
The glial glutamate transporter GLT-1 may be the predominant
Na+-dependent glutamate transporter in forebrain.
Expression of GLT-1 correlates with astrocyte maturation in vivo and
increases during synaptogenesis. In astrocyte cultures, GLT-1
expression parallels differentiation induced by cAMP analogs or by
coculturing with neurons. Molecule(s) secreted by neuronal cultures
contribute to this induction of GLT-1, but little is known about the
signaling pathways mediating this regulation. In the present study, we
determined whether growth factors previously implicated in astrocyte
differentiation regulate GLT-1 expression. Of the six growth factors
tested, two [epidermal growth factor (EGF) and transforming growth
factor-
] induced expression of GLT-1 protein in cultured
astrocytes. Induction of GLT-1 protein was accompanied by an increase
in mRNA and in the Vmax for
Na+-dependent glutamate transport activity. The effects of
dibutyryl-cAMP and EGF were additive but were independently blocked by
inhibitors of protein kinase A or protein tyrosine kinases,
respectively. The induction of GLT-1 in both EGF- and
dibutyryl-cAMP-treated astrocytes was blocked by inhibitors targeting
phosphatidylinositol 3-kinase (PI3K) or the nuclear transcription
factor-
B. Furthermore, transient transfection of astrocyte cultures
with a constitutively active PI3K construct was sufficient to induce
expression of GLT-1. These data suggest that independent but converging
pathways mediate expression of GLT-1. Although an EGF receptor-specific
antagonist did not block the effects of neuron-conditioned medium, the
induction of GLT-1 by neuron-conditioned medium was completely
abolished by inhibition of PI3K or nuclear factor-B. EGF also
increased expression of GLT-1 in spinal cord organotypic cultures.
Together, these data suggest that activation of specific signaling
pathways with EGF-like molecules may provide a novel approach for
limiting excitotoxic brain injury.
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